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The physiopathological evolution of prostate cancer Antonello Di Paolo

The physiopathological evolution of prostate cancer Antonello Di Paolo Dipartimento di Medicina Clinica e Sperimentale Università di Pisa. Androgens are key players in prostate cancer proliferation. Selective pharmacological pressure and adaptation in prostate cancer.

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The physiopathological evolution of prostate cancer Antonello Di Paolo

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  1. The physiopathological evolution of prostate cancer Antonello Di Paolo Dipartimento di Medicina Clinica e Sperimentale Università di Pisa

  2. Androgens are key players in prostate cancer proliferation

  3. Selectivepharmacologicalpressure and adaptation in prostate cancer Selectivepressure Adaptation Knudsen KE, Penning TM. Trends EndocrinolMetab 2010; 21: 315-324

  4. CRPC isnotandrogenindependent • Androgen-dependent signaling mediates prostate cancer growth despite castrate levels of serum testosterone • Mechanisms: • Increased androgen uptake • Increased AR ligand synthesis • Receptor overexpression/amplification • AR mutations (eg, hypersensitivity) • Ligand-independent AR activation Sharifi N, et al. J Investig Med. 2010;58:938-944. Dutt SS, et al. Future Oncol. 2009;5:1403-1413.

  5. CRPC isnotandrogenindependent Knudsen KE, Penning TM. Trends EndocrinolMetab 2010; 21: 315-324

  6. AR gene PTEN gene Tumorsuppressorgenes Grasso et al. Nature. 2012; 487: 239–243

  7. AR mutation and gainoffunction LNCaP M.C. privo di androgeni LNCaP-cDx LNCaP-hr Bicalutamide Bicalutamide no 1 μM Hara et al. Cancer Res 2012; 63: 149-153

  8. AR gene mutations Transactivation assays showed that bicalutamide worked as an agonist for both W741C and W741L mutant ARs Hara et al. Cancer Res 2012; 63: 149-153

  9. Alternative splicingof AR gene Hu et al. Cancer Res 2009; 69: 16-22

  10. High gene expressionof AR splicingvariants in hormone-refractoryPCa AR 11x AR-V1 22x AR-V7 20x HRPC, hormone-refractoryPCa Hu et al. Cancer Res 2009; 69: 16-22

  11. Post-translationalmodificationsof AR Gioeli & Paschal. MolCellEndocrinol 2012; 352: 70–78

  12. Post-translationalmodificationsof AR Gioeli & Paschal. MolCellEndocrinol 2012; 352: 70–78

  13. CellcycleregulationfromG0to G1-S Mitogens Ras/Raf/MAPK D-type cyclins CDK4/6 CDK4/6-cyclin D CDK2 G1-S transition Cyclin E pRB/p107/p130 DP(1,2) CDK2-cyclin E E2Fn-DPn E2F(1-6) Phosphorylation of proteins involved in histone modification, DNA replication and repair, centrosome duplication and maturation Recruitment of repressor complexes such as histone deacetylases and chromosomal remodeling SWI/SNF complexes

  14. “…cyclinD1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b–mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease…” Augello et al. J Clin Invest. 2013;123(1):493–508

  15. Intracrineandrogensynthesis Cancer Res 2006;66:2815-2825

  16. “…the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT…”

  17. AndrostenedionesustainsPCaxenograftgrowth in castratedmice

  18. Increasedbioavailabilityofprecursors A1 [ T ] normal transcription activity A2 [ C ] increased transcription activity -34T>C Medianoverallsurvival: A1, 7.6 yearsvs. A2, 8.9 years (p<0.040 bylog-rank test) Hamada et al. Urology 2007; 70: 217-220

  19. Increasedcellularuptake in PCa “The superfamily oforganicanion-transportingpolypeptides (OATP), encodedby SLCO genes, mediates the … uptakeofvariousendogenouscompounds and drugsintocells…SLCO2B1and SLCO1B3havebeenshowntobeinvolved in the steroidhormoneuptake. SLCO2B1 … mediates the transportofsteroidconjugates, suchas DHEAS and estrone-3-sulfate. SLCO1B3 [is] involved in the uptakeofseveralhormonesincludingT” J ClinOncol 2011; 29: 2565-2573

  20. SLCO2B1 SNPs are associatedwithincreased gene expression and cellgrowthin vitro Yang et al. J ClinOncol 2011; 29: 2565-2573

  21. SLCO2B1 SNPs and TTP Yang et al. J ClinOncol 2011; 29: 2565-2573

  22. SLCO2B1-SLCO1B3 SNPs and TTP Yang et al. J ClinOncol 2011; 29: 2565-2573

  23. Stemcells in prostate cancer Mimeault & Batra. BiochimBiophysActa 2011; 1816: 25–37

  24. Epigenetics in prostate cancer Shen& Pili. Cancer J 2008;14:46-53

  25. Epigenetics in prostate cancer Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development and function, as well as malignant transformation. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. AR as a globally acting transcriptional repressor. This repression is mediated by androgen-responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell–like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous dedifferentiation. Zhaoet al. GenomeRes 2012; 22: 322-331

  26. AR directlyregulates a largenumberof target genes Zhaoet al. GenomeRes 2012; 22: 322-331

  27. Expressionofsteroidogenicenzymesincastration-resistantmetastases versus primaryprostate Montgomery et al. CancerRes 2008; 68: 4447-4454

  28. Mean tissue androgen levels in castration-resistant metastases from anorchid patients versus primary prostate tissues from eugonadal men 29 Montgomery et al. CancerRes 2008; 68: 4447-4454

  29. Conclusion Advanced prostate cancer is neither hormone refractory nor androgen independent and remains nuclear steroid receptor driven Several adaptive pathways may sustain cancer growth Androgen receptor acts as a transcriptional repressor, which maintains a stem cell-like undifferentiated state The complex and redundant biochemical network behind CRPC may offer several “drugable” targets and biomarkers for patients’ stratification

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